KR840002066B1 - Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one - Google Patents
Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one Download PDFInfo
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Abstract
Description
본 발명은 5-Q-[3,4'-비피리딘]-6(1H)-온(Q : 시아노기 또는 카르바밀기)제조 중간체로 유용한 신규의 N- [3-디메틸아미노-2-(4-피리딘일 )-2-프로페닐리덴]-N-메틸메탄이미늄염의 제조방법에 관한 것이다.The present invention provides novel N- [3-dimethylamino-2- (useful as an intermediate for preparing 5-Q- [3,4'-bipyridin] -6 (1H) -one (Q: cyano or carbamyl). A method for producing 4-pyridinyl) -2-propenylidene] -N-methylmethaneiminium salt.
이 신규의 중간체 또는 염을 사용하여 심장수축성을 증가시키는데 사용되며 또한 강심제로서도 사용할수 있는 것이다.The new intermediates or salts are used to increase cardiac contractility and can also be used as cardiac agents.
미국특허 제 4,004,012호에는 ,12-디히드로-2-옥소-5-(피리딘일)니코티노니트릴 제조방법과 이것을 가수분해하여 상응하는 니코틴아미드로 전환시키는 두가지 방법이 나와 있다.U.S. Patent No. 4,004,012 discloses a process for preparing 12-dihydro-2-oxo-5- (pyridinyl) nicotinonitrile and two methods of hydrolyzing and converting it to the corresponding nicotinamide.
그 한가지 방법은 1,2-디히드르-2-옥소-5-(피리딘일)니코틴 아미드를 만드는 것이고, 이어서 니코틴아미드를 상응하는 3-아미노 화합물로 전환시키는 방법이 두번째 방법이다. 이들 두가지 방법은 모두가 (1) α-(피리딘일)-β-(R1R2N)아크롤레인과α-시아노아세트아미드를 염기성 응축제 존재하, 즉 에톡시화나트륨 또는 에톡시화 나트륨 같은 저급 알콕시화 알칼리를 메탄올 또는 에탄올 같은 저급 알칸올중에 가한 용액존재하에 반응시키거나,(2) α-(피리딘일)-말론알데히드와 α-시아노아세트아미드를 모로폴린 또는 피페리딘 또는 이들의 아세트산염 같은 촉매성 응축제 존재하에 가열하므로서 1,2-디히드로-2-옥소-5-(피리딘일)-니코티노니트릴을 제조하는 방법에 관한것이다. 미국특허 제4,004,012호의 실시예 A-1에서 나온 바와같이 방법(1)의 생성물을 나트륨염으로 수집하여 재결정시킨 후 염산으로 처리하므로 1,2-디히드로-2-옥소-5-(파라단알)니코티노니트릴로 전환시키고 있다. 또한 α-(피리딘일)-β-(R1R2N)아크롤레인과 말 론아미드를 반응시켜 1,2-디히드로-2-옥소-5-(피리딘일)니코틴아미드를 제조하는 방법이 대해서도 나와있다.One way is to make 1,2-dihydr-2-oxo-5- (pyridinyl) nicotin amide, followed by the conversion of nicotinamide to the corresponding 3-amino compound. Both of these methods use (1) α- (pyridinyl) -β- (R 1 R 2 N) acrolein and α-cyanoacetamide in the presence of a basic condenser, i.e. lower ethoxide or sodium ethoxylated The alkoxylated alkali is reacted in the presence of a solution added in lower alkanols such as methanol or ethanol, or (2) α- (pyridinyl) -malonaldehyde and α-cyanoacetamide are morpholine or piperidine or acetic acid thereof A method for preparing 1,2-dihydro-2-oxo-5- (pyridinyl) -nicotinonitrile by heating in the presence of a catalytic condensing agent such as a salt. As described in Example A-1 of US Pat. No. 4,004,012, the product of Method (1) was collected with sodium salt, recrystallized and treated with hydrochloric acid, thus 1,2-dihydro-2-oxo-5- (paradanal) It is being converted to nicotinonitrile. There is also a method for producing 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinamide by reacting α- (pyridinyl) -β- (R 1 R 2 N) acrolein with malonamide. Listed.
최근에 나온 폴란드 논문[Current Abstracts of Chemistry, Vol.74,Issue 814, Item 285573, 1978]에서는 3-디메틸아미노-2-(4-피리딘일)아크롤레인[β-(디메틸아미노)-α-(4-피리딘일) 아크롤레인과 같음]과 말로노니트릴을 메톡시화나트륨과 메탄올로 된 용액존재하에 반응시켜 2-메톡시-5-(4-피리딘일)니코티노니트릴을 제조하고 있다.A recent Polish article [Current Abstracts of Chemistry, Vol. 74, Issue 814, Item 285573, 1978] describes 3-dimethylamino-2- (4-pyridinyl) acrolein [β- (dimethylamino) -α- (4 -Pyridinyl) same as acrolein] and malononitrile are reacted in the presence of a solution of sodium methoxide and methanol to prepare 2-methoxy-5- (4-pyridinyl) nicotinonitrile.
아놀드[Arnold, Coll, Czech, Chem. Comm.28, 863 868(1963)]에 의하면 β-디메틸딜아미노-α-(4-피리딘일)아크롤레인을 제조하는 세가지 방법으로서는 (a) 4-피콜린과 디메틸포름아미드 및 옥시염화인을 포르밀화 반응시키거나,(b) 4-피콜린과 디메틸포름아미드 및 포스겐을 클로로포름중에서 포르밀화 반응시키는 방법들이 있다고 했다.Arnold, Arnold, Coll, Czech, Chem. Comm.28, 863 868 (1963)] described three methods for preparing β-dimethyldilamino-α- (4-pyridinyl) acrolein: (a) 4-picoline, dimethylformamide and phosphorus oxychloride. It is known that there is a method of performing a densification reaction or (b) formylation of 4-picolin with dimethylformamide and phosgene in chloroform.
본 발명의 한가지 특징에서 본다면 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄염을 다음과 같은 구조식 I의 결정질 형태 또는 이것의 산첨가염으로 제조함에 있는 것이다.In one aspect of the invention, the N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium salt is prepared in the crystalline form of formula I or an acid thereof It is to prepare as an addition salt.
[도식][scheme]
위의 식에서 An-은 약학적으로 섭취가능한 산의 음이온이다.An- in the above formula is an anion of a pharmaceutically acceptable acid.
이 화합물은 다음에 나오는 바와같이 중간체로서 사용할 수 있을 뿐만 아니라 표준 강심제 시험에서도 강심효과가 있는 것이다.This compound can be used as an intermediate as shown below and has a cardiac effect in a standard cardiac test.
적합한 유리염기형은 An-으로서 Cl-을 가지는 구조식 I 인데, 즉 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 염화물이며,Suitable freebase forms are of formula I having Cl- as An-, ie N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride,
이것의 적합한 산첨가염은 염산염, 즉 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드염산염이다. 첫번째 반응에 있어서 4-피콜린 1몰당 최소한 3몰 당량의 포스겐과 4-피콜린 1부피당 최소한 5-10부피 과잉량의 디메틸포름아미드를 4-피콜린을 혼합하고 50-80℃로 가열하여 서서히 반응시켜 반응혼합물을 냉각하므로서 결정형태의 N- [3-디메틸아미노-2-(4-피리딘일 )-2-프로페닐리덴]-N-메틸메탄이미늄염 클로라이드 염산염(An-이 염화이온인 I의 HCl염)을 제조한다. 두번째 반응이 Q-CH2CONH2와 최소한 3몰당량의 염기와의 혼합물을 무수매체중에서 N- [3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄염 클로라이드 염산염과 혼합하고 60-100℃에서 가열한후 이 반응 혼합물을 중화하므로서 5-Q-[3,4'-비피리딘]-6(1H)-온(Q는 시아노기 또는 카르바밀기)을 제조하는데, 위의 두가지 생성물은 강심제인 암리논, 즉 아미노-[3,4'-비피리딘]-6(1H)-온 제조시에 중간체로 알려져 있는 것이다.Suitable acid addition salts thereof are hydrochloride, ie N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride. In the first reaction, at least 3 molar equivalents of phosgene per mole of 4-picoline and at least 5-10 volume excess of dimethylformamide per volume of 4-picoline were mixed with 4-picoline and slowly heated to 50-80 ° C. Reacting to cool the reaction mixture to form crystalline N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimine salt chloride hydrochloride (I where I- is chloride ion) HCl salt) is prepared. The second reaction is a mixture of Q-CH 2 CONH 2 with at least 3 molar equivalents of base in N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methyl in anhydrous medium. 5-Q- [3,4'-bipyridin] -6 (1H) -one (Q is a cyano group or carba) by mixing with methaneimide salt chloride hydrochloride and heating at 60-100 ° C. to neutralize the reaction mixture. The two products above are known as intermediates in the preparation of the cardiac agent amlinone, ie amino- [3,4'-bipyridin] -6 (1H) -one.
위의 두가지 반응을 결합하여 2차 반응에서 5-Q-[3,4'-비피리딘]-6(1H)-온을 생성시킴에 있어서 1차 반응에서 생성된 결정형태의 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염을 직접 사용할 수 있다. 본 방법에 있어서의 특이한 장점은 1차 반응에서 침전이 일어나면 거의 정량적으로 N-[3-메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염이 생성되므로 β-디메틸아미노-α-(4-피리딘일-아크롤인을 생성시키고자 액상에서의 냉각과 중화를 시킬 필요가 없다는 것이다. 또한 1차 반응에서 거의 정량적인 수득율이 나오므로 해서 두가지 단계에서 전반적으로 수득율이 높아지게 되는 것이다.The combination of the two reactions above yields 5-Q- [3,4'-bipyridin] -6 (1H) -one in the secondary reaction, the crystal form of N- [3- in the primary reaction. Dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride can be used directly. A particular advantage of this method is that N- [3-methylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride almost quantitatively when precipitation occurs in the first reaction. This eliminates the need for cooling and neutralizing in the liquid phase to produce β-dimethylamino-α- (4-pyridinyl-acroline), and also provides two quantitative yields in the first reaction. In general, the yield will be increased.
반응 혼합물에서 여과 또는 상청 반응액을 제거하므로서 분리한 후 그 다음 단계에서 바로 중간체인 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클라이드 염산과 Q-CH2CONH2및 염기를 그대로 반응시킬 수 있다.The reaction mixture was separated by filtration or by removing the supernatant, and the next step was an intermediate, N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethaneimide. It is possible to react the chromium hydrochloride with Q-CH 2 CONH 2 and the base as it is.
심장 수축성을 증가시키는 강심제 조성물은 약학적으르 섭취가 되는 비활성 운반체와 이것의 활성 성분으로서 강심제인 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄(I )또는 이것의 약학적으로 섭취가 가능한 산첨가염의 유효량으로 되어 있다.Cardiovascular compositions that increase cardiac contractility include inert carriers that are ingested pharmacologically and N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N- It is an effective amount of methylmethaneimium (I) or a pharmaceutically acceptable acid addition salt thereof.
환자의 심장 수축성을 크게하기 위한 치료에 있어서는 고체 또는 액체로 된 투여 형태를 강심제인 N-[3-디메틸아미노-3-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄(1) 또는 약학적으로 섭취가 가능한 이것의 산첨가염 유효량을 환자에게 경구투여 또는 비경구 투여한다.In the treatment for increasing the heart contraction of the patient, the solid or liquid dosage form is used as the cardiac agent N- [3-dimethylamino-3- (4-pyridinyl) -2-propenylidene] -N-methylmethaneimide. Either or parenterally administer to the patient an effective amount of nium (1) or a pharmaceutically acceptable acid addition salt thereof.
N-[3-데메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 염(I )은 유리 염기형태 및 산첨가염 형채로 사용되는데, 이 두가지 형태는 본 발명의 범위에 속하는 것들이다. 산첨가염은 단순히 사용하기 훨씬 편리한 형태이고 실제로 염형태로 사용하면 염기 형태로 사용하는 것과 갈다. 산염가염을 제조하는데 사용할 수 있는 산으로는 유리염기와 결합했을때 약학적으로 섭취가 가능한 염, 즉 음이온이 비교적 동물조직이 해독이 없는 염을 생성할 수 있는 것으로 사용하므로서 유리염기에 고유한 유익한 강심제 특성이 음이온에 의한 부작용으로 저하되지 않아야 하는 것이다.N- [3-demethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethaneimium salt (I) is used in free base form and in acid addition salt form. The forms are those falling within the scope of the present invention. Acid addition salts are simply more convenient forms of use, and when used in salt form, are in contrast to those used in base form. Acids that can be used to prepare acid salts are those that are inherently beneficial to free bases because they can be used to produce pharmaceutically ingestible salts, i.e., anions that are relatively non-detoxible to animal tissue when combined with free bases. Cardiac properties should not be degraded by adverse effects caused by anions.
본 발명을 실시함에 있어서 An이 염화이온인 이미늄 클로라이드 염산염을 직접 제조할 수 있다.In carrying out the present invention, iminium chloride hydrochloride in which An is chloride ion can be prepared directly.
그려나 이 화합물을 An이 Cl-이외의 것인 염으로 전환시킬 수 있으며, 필요에 따라서는 산천가염과 염기를 중화시킬때 유리염기를 분리시킨다. 이미늄 클로라이드 염산염을 기타 양이온의 염으로 전환시킬때는 클로라이드 염산염의 수용액을 수산화물 형태의 음이온 교환수지로 처리하여 염을 상응하는 이미늄수산화물로 전환시킨다. 이것을 소요의 산으로 산성화하므로서 산에 상응하는 음이온(An)을 가진 염을 산에 상응하는 산천가염 형태로 얻는다. 원래의 음이온의 염에 비해 전환된 형에 있어서 거의 저하된 용해도를 가진 산을 사용하므로서 한가지 음이온을 다른 음이온으로 전환시킬 수 있는데, 즉 과염소산과의 반응에 의해 클로라이드 염산염을 과염소산 히드로 과염소산염으로 전환시키는 것이다. 염을 메탄올에 용해또는 현탁시키면서 몰당량의 메톡시화 나트륨을 첨가하여 염화나트륨이 침전시켜 산첨가염을 유리염기로 전환시키는데 이것은 비교적 메탄올에 불용성이다. 여액을 농축하여 유리 염기를 회수한다.The compound can then be converted to a salt where An is other than Cl- and, if necessary, separates free base when neutralizing acid salts and bases. When converting iminium chloride hydrochloride to salts of other cations, the aqueous solution of chloride hydrochloride is treated with an anion exchange resin in hydroxide form to convert the salt to the corresponding iminium hydroxide. By acidifying this with the required acid, a salt with an anion (An) corresponding to the acid is obtained in the form of an acid salt corresponding to the acid. By using an acid with nearly reduced solubility in the converted form compared to the salt of the original anion, one anion can be converted to another, i.e., by converting chloride hydrochloride to perchloric acid hydroperchlorate by reaction with perchloric acid. will be. Sodium chloride precipitates by adding a molar equivalent of sodium methoxylated while the salt is dissolved or suspended in methanol, converting the acid addition salt to a free base, which is relatively insoluble in methanol. The filtrate is concentrated to recover the free base.
본 발명의 범위에 속하는 기타 적절한 약학적으로 섭취가 되는 염은 브롬화 수소산, 황산, 인산 및 술팜산과 같은 무기산, 아세트산, 락트산, 시트르산, 타르타르산, 메탄술폰산, 에탄술폰산, 벤젠술폰산, p-톨루엔술폰산, 시클로헥실술팜산, 퀸산 등과 같은 유기산으로서 이들로 부터 유도된 것들인데, 이들 산은 각각 브롬화 수소산염, 황산염, 인산염, 술팜산염, 아세트산염, 락트산염, 시트르산염, 타르타르산염, 메탄술폰산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 시클로헥실술팜산염 및 퀀산염 을 생성한다. 위의 산첨가염은 클로라이드 염산염을 다른 음이온, An(An은 산첨가염의 양이온과 같음)으로 전환시켜 얻는다.Other suitable pharmaceutically ingestible salts within the scope of the present invention include inorganic acids such as hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid, acetic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Organic acids such as cyclohexylsulfamic acid, quinic acid, etc., derived from them, which are hydrobromide, sulfate, phosphate, sulfamate, acetate, lactate, citrate, tartarate, methanesulfonic acid, ethanesulfonic acid, respectively Salts, benzenesulfonates, p-toluenesulfonic acid salts, cyclohexylsulfate salts and quantates. The acid addition salts above are obtained by converting the chloride hydrochloride to another anion, An (An is the same as the cation of the acid addition salt).
분리된 유리 염기의 산천가염은 적당한 산을 함유한 적당한 용매 또는 알코올 수용액에 유리 염기를 용해하여 용액을 증발시켜 염을 분리하거나 유기용매중에서 유리염기와 산을 반응시켜 제조할 수도 있는데,어느 경우에 있어서나 염은 직접 분리되거나 용액을 원심분리하므르서 염을 얻는다.Acid base salts of the separated free bases may be prepared by dissolving the free base in a suitable solvent or alcohol solution containing a suitable acid to evaporate the solution to separate the salts or by reacting the free base with an acid in an organic solvent. However, the salts are separated directly or the solution is centrifuged to obtain the salts.
염기성 화합물의 약학적으로 섭취가 가능한 염이 좋다고 하지만 산첨가염 모두가 본 발명의 범위에 속한다. 경제 또는 확인 목적으르서만 염을 생성시킬 경우나 이온 교환절차에 따라 약학적으로 섭취가 가능한 염을 제조할 때 중간체로 사용할 경우에 있어서도 특정한 염 그 자체가 중간 생성물로서 사용될 뿐이라 하더라도 모든 산천가염을 유리염기의 공급원으로 사용할 수 있다.Although pharmaceutically acceptable salts of basic compounds are preferred, all acid addition salts are within the scope of the present invention. Even when salts are produced only for economic or identification purposes, or when they are used as intermediates in the preparation of pharmaceutically ingestible salts according to ion exchange procedures, all acid salts may be used, even if the particular salt itself is used as an intermediate product. Can be used as a source of free base.
본 발명에 의한 방법에 따라 제조한 생성물의 분자 구조 적외선 분석, 핵자기공명 분석 및 질량 스펙트럼 분석, 크로마토그래피에 의한 이동성 및 각 시료에 대한 원소분석에 계산치와 실험치에 의해 나타난자료에 입각하여 확인했다.Molecular structure of the product prepared according to the method according to the present invention was confirmed based on the data indicated by the calculated value and experimental value in the infrared analysis, nuclear magnetic resonance analysis and mass spectrum analysis, mobility by chromatography and elemental analysis for each sample. .
화학기슬자가 실시할 수 있도록 본 발명의 실시방법을 하자면 다음과 같다. 즉 4-피콜린 1몰당 최소한3몰당량의 포스겐과 과잉량의 디메틸포름아미드를 사용하여 4-피콜린으로 부터 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염을 제조하는 방법에 있어서 디메틸포름아미드에 포스겐을 약 -10℃ -0℃에서 적하하고 차거운 용액에 온도를 25℃이하, 가능하면 0℃-20℃사이로 유지하여 4-피콜린을 서서히 첨가한 후 반응혼합물을 50-80℃정도, 가능하면 60-65℃정도에서 가열하는 것이다. 또 다른 방법으로는 포스겐을 기포로 만들어 0°-10℃로 유지된 디메틸포름아미드에 송입한다. 이 반응 혼합물을 실온까지 냉각하면 이미늄 클로라이드 염산염이 정량적으로 분리된다. 4-피클린 1부피당 디메틸포름아미드 약 10부피를 사용한 것이 좋았다. 그려나 4-피콜린 1부피당 디메탈포름아미드 5부피정도를 사용한 결과 반응이 만족스럽게 진행되었다.4-피콜린 1부피당 디메틸포름아미드 약 20-25부피를 사용할 수 있지만 10부피사용한데 비해 하등의 장점이 없었다.According to the embodiment of the present invention so as to be carried out by the chemical chaser. N- [3-dimethylamino-2- (4-pyridinyl) -2-propenyl from 4-picoline, using at least 3 molar equivalents of phosgene and excess dimethylformamide per mole of 4-picoline. Phosgene is added dropwise to dimethylformamide at about −10 ° C. −0 ° C. and the temperature in the cold solution is below 25 ° C., preferably between 0 ° C.-20 ° C. 4-picoline is added slowly, and the reaction mixture is heated at about 50-80 ° C, if possible, at about 60-65 ° C. Alternatively, phosgene is bubbled and fed into dimethylformamide maintained at 0 ° -10 ° C. Cooling this reaction mixture to room temperature quantitatively separates iminium chloride hydrochloride. It is preferred to use about 10 volumes of dimethylformamide per volume of 4-piclin. The reaction proceeded satisfactorily by using about 5 volumes of dimetalformamide per 1 volume of 4-picoline. About 20-25 volumes of dimethylformamide per volume of 4-picoline could be used, but 10 volumes were used. There was no advantage.
무수물 매체중에서 최소한 3몰당량의 염기와 Q-CH2CONH2를 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페널리덴]-N-메탈메탄이미늄 클로라이드 염산염과 반응시킨 후 반응 혼합물을 중화시켜 용액중에서 5-Q-[3,4'-비피리딘]-6(1H)-온의 양이온 금속염을 5-Q-[3,4'-비피리딘]-6(1H)-온으로 전환시키는 방법에 있어서(이때 중성 및 약산성 용액에서 침전으로되어 생성됨), 반응물을 혼합할때Q-CH2CONH2와 염기를 혼합한후 염기가 이미늄 염과 접촉하게 하던지 염을 부분 가수분해하여 Q-CH2CONH2와 반응시켜 반응을 편리하게 진행시킬 수 있는데, 이때 생성물의 수득율은 저하된다. 반응물을 증기탕중에서 60-100℃로 가열하면 반응이 완결된다.N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-metalmethaneimide chloride hydrochloride with at least 3 molar equivalents of base and Q-CH 2 CONH 2 in anhydride medium The reaction mixture was neutralized by reaction with a cationic metal salt of 5-Q- [3,4'-bipyridin] -6 (1H) -one in the solution, followed by 5-Q- [3,4'-bipyridine] -6 In the method of conversion to (1H) -one (which is produced by precipitation in neutral and weakly acidic solutions), the base is brought into contact with the iminium salt after mixing the base with Q-CH 2 CONH 2 when mixing the reactants. The salt can be partially hydrolyzed and reacted with Q-CH 2 CONH 2 to facilitate the reaction, with the yield of product being lowered. The reaction is completed by heating the reaction to 60-100 ° C. in a steam bath.
저급 알칸올(탄소수 1-4개) 또는 쌍극의 비양자성 용매, 중에 첨가한 강염기, 즉 메톡시화나트륨, 수산화나트륨 모는 무수 탄산칼륨을 디메틸포름아미드에 가한것, 메톡시화나트륨, 수산화칼륨 및 3 : 1=무수 탄산칼륨 : 수산화칼륨을 메탄올에 가한 것, 수소화나트륨을 디메틸포름아미드와 t-부탄올에 가한것,에탄올 또는 이소프로필 알코올에 메톡시화 나트륨을 가한것, N,N-디메틸아세트아미드 또는 피리딘에수소화나트륨을 가한 것등을 사용하여 반응을 진행시킨다. 기타 쌍극성의 비양자성 용매로 사용할 수 있는 것들로는 아세토니트릴과 술폭시화 디메틸이 있다. 메톡시화 나트륨을 염기로 사용할 경우 나트륨염인 양이온 염으로서의 생성물인 5-Q-[3,4'-비피리딘]-6(1H)-온은 여과에 의해 반응 혼합물로 부더 편리하게 분리된다. 생성물의 양이온염 형태는 물에 용해하며 용액중에서 아세트산 같은 산을 첨가하여 중화하므로서 pH 약 5.0-6.5, 가능하면 약 6.0-6.5의 약산성으로 만들어 4-피콜린으로 부터 5-Q[3,4'비피리딘]-6(1H)-온을 극히 좋은 수득율로 침전시킨다.Lower alkanols (1-4 carbon atoms) or bipolar aprotic solvents, strong bases added in ie sodium methoxide, sodium hydroxide, added anhydrous potassium carbonate to dimethylformamide, sodium methoxide, potassium hydroxide and 3: 1 = potassium anhydride: potassium hydroxide added to methanol, sodium hydride added to dimethylformamide and t-butanol, sodium methoxylated to ethanol or isopropyl alcohol, N, N-dimethylacetamide or pyridine The reaction is carried out by adding sodium hydride or the like. Other bipolar aprotic solvents that may be used include acetonitrile and sulfoxylated dimethyl. When sodium methoxylated is used as the base, 5-Q- [3,4'-bipyridin] -6 (1H) -one, the product of the cationic salt as the sodium salt, is more conveniently separated into the reaction mixture by filtration. The cationic salt form of the product is dissolved in water and neutralized by the addition of an acid such as acetic acid in the solution, resulting in a slightly acidic pH of about 5.0-6.5, possibly around 6.0-6.5, from 4-picoline to 5-Q [3,4 ' Bipyridin] -6 (1H) -one is precipitated with extremely good yield.
본 발명을 실시예에 따라 상술하기로 한다.The present invention will be described in detail according to the embodiment.
[실시예 1]Example 1
N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염제조N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethaneimium chloride hydrochloride
포스겐(213㎖,98.7g,3.0몰)을 건조한 시약 디메틸 포름아미드 1940㎖(73g, 25몰)에 교반하면서 적하하고 -10° -10℃에서 냉각했다.Phosgene (213 ml, 98.7 g, 3.0 mol) was added dropwise to 1940 ml (73 g, 25 mol) of dry reagent dimethyl formamide while cooling at -10 ° -10 ° C.
냉각을 계속하고 4-피콜린(97.3㎖,93.1g,1.0몰)을 교반하면서 5분이상에 걸쳐 서서히 첨가했다. 1시간 이상에 걸처 35-40℃로 온도가 상승하면서 발열반응이 되었다. 혼합물을 60-65℃에서 3시간 교반가열한 후 실온으로 냉각하고 여과했다. 디메틸 포름아미드와 에테르를 사용하여 필터케이크를 연속 세척한 후 건조(50℃,0.1Torr,4시간)하므로서 회황색결정의 N-[3-다메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염 (m. p.150-155℃, 분해, 밀봉한 모세관 중에서)을 얻었다. 수득율 : 271g, 98%.Cooling was continued and 4-picoline (97.3 mL, 93.1 g, 1.0 mole) was added slowly over 5 minutes with stirring. The temperature rose to 35-40 ° C. over 1 hour, resulting in an exothermic reaction. The mixture was stirred and heated at 60-65 ° C. for 3 hours, then cooled to room temperature and filtered. Continuous washing of the filter cake with dimethyl formamide and ether followed by drying (50 ° C., 0.1 Torr, 4 hours) to give N- [3-dimethylamino-2- (4-pyridinyl) -2 as an off-yellow crystal. -Propenylidene] -N-methylmethanimium chloride hydrochloride (mp150-155 DEG C, in a decomposed, sealed capillary) was obtained. Yield: 271 g, 98%.
동일한 량의 반응물과 방법을 사용하여 반응 혼합물을 60-65℃에서 2시간 가열하므로서 다른 반응을 시킨결과 생성물 26.9g(97%수득율)을 얻었다. 생성물중 125g을 디메틸포름아미드에서 재결정하고 건조디메틸포름 아미드 100㎖씩 2회 세척한후 에테르 100㎖씩 2회 세척하고 회전식 증발기에서 40℃에서0.1Torr하에 건조하여 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염(m.p.153-158℃, 분해, 밀봉한 모세관중에서)을 얻었다.Another reaction was carried out by heating the reaction mixture at 60-65 ° C. for 2 hours using the same amount of reactants and methods to give 26.9 g (97% yield) of the product. 125 g of the product was recrystallized from dimethylformamide, washed twice with 100 ml of dry dimethylformamide, twice with 100 ml of ether, and dried at 0.1 Torr at 40 ° C. in a rotary evaporator to give N- [3-dimethylamino-2. -(4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride (mp153-158 DEG C, in a decomposed and sealed capillary tube) was obtained.
[실시예 2]Example 2
5-시아노-[3,4'-비피리딘]-6(1H)-온 제조Preparation of 5-cyano- [3,4'-bipyridin] -6 (1H) -one
[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염 27.69(0.1몰),α-시아노 아세트 아미드 9.3g(0.11몰), 무수 탄산칼륨 41.5g(0.3몰) 및 건조한 디메틸포름아미드 250㎖로 된 혼합물을 증기중탕중에서 1시간 동안 가열한 후 냉각했다. 생성물은 칼륨염인 침전된 고체로서 이것을 수집하여 공기건조한 후 물에 용해하여 그 용액을 아세트산으로 pH 약 5인 약산으로 만들었다. 분리된 고체 생성물을 수집하여 물, 에탄올 및 에테르로 연속 세척한 후 건조하므르서 5-시아노-[3,4'-비피리딘]-6(1H)-온(m.p.>300℃)8g을 얻었다.[3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride 27.69 (0.1 mol), α-cyano acetamide 9.3 g (0.11 mol), anhydrous A mixture of 41.5 g (0.3 mol) of potassium carbonate and 250 ml of dry dimethylformamide was heated in a steam bath for 1 hour and then cooled. The product was a precipitated solid which is a potassium salt, which was collected, air dried and dissolved in water to make the solution a weak acid having a pH of about 5 with acetic acid. The separated solid product was collected, washed successively with water, ethanol and ether and dried to give 8 g of 5-cyano- [3,4'-bipyridin] -6 (1H) -one (mp> 300 ° C). .
위의 모액을 진공에서 가열하여 액체를제거하고 고체 잔류물을 물(약 1ℓ)에 용해한 수용액을 아세트산으로 pH 약 5까지 중화한후 분리된 고체를 수집하여 물, 에탄올 및 에테르로 연속 세척하고 진공에서80℃에서 하루밤 건조하므로서 다시 5-시아노-[3,4'-비피리딘]-6(1H)-온(m. p.>300℃ 9g을 얻었다.The mother liquor was heated in vacuo to remove the liquid, and the aqueous solution of the solid residue dissolved in water (about 1 l) was neutralized with acetic acid to pH about 5, and the separated solids were collected and washed successively with water, ethanol and ether and vacuumed. 5 cyano- [3,4′-bipyridin] -6 (1H) -one (mp> 300 ° C. 9g was obtained again by drying at 80 ° C. overnight.
[실시예 3]Example 3
5-카르바밀-[3,4'-비피리딘]-6(1H)-은 제조5-Carbamyl- [3,4'-bipyridine] -6 (1H) -silver preparation
광물성 기름에 분산시킨 50%수소화나트륨(0.25몰) 12g을 미분말 말론아미드 11.2g(0.11몰)과 건조된디메틸포름아미드 200㎖로 된 혼합물에 첨가하고 실온에서 15분간 교반했다.12 g of 50% sodium hydride (0.25 mol) dispersed in mineral oil was added to a mixture of 11.2 g (0.11 mol) of fine powder malonamide and 200 ml of dried dimethylformamide and stirred at room temperature for 15 minutes.
이 교반혼합물에 3-디메틸 아미노-2-(4-피리딘일)-2-프로펜-1-일리덴3-dimethyl amino-2- (4-pyridinyl) -2-propene-1-ylidene is added to this stirred mixture.
디메틸 암모늄 클로라이드 염산염 27.6g(0.1몰)을 첨가한 결과 발열 반응이 일어나서 온도가 65℃정도로 상승했다. 이 반응혼합물을 증기탕중에서 1시간 가열한 후 냉각했다. 분리된 고체(생성물의 나트륨염)를 수집하여 온수 1.7ℓ에용해한 수용액을 아세트산으로 pH 약 5정도까지 중화했다. 생성된 침전을 수집하고 물, 에탄올 및 에테르로 연속 세척한 후 진공에서 80℃에서 하루밤 건조하므로서 5-카르바밀-[3,4'-비파리딘]-6(1H)-온(m.p. 300℃)16g을 얻었다.When 27.6 g (0.1 mol) of dimethyl ammonium chloride hydrochloride was added, an exothermic reaction occurred and the temperature rose to about 65 ° C. The reaction mixture was heated in a steam bath for 1 hour and then cooled. The separated solid (sodium salt of the product) was collected and the aqueous solution dissolved in 1.7 L of warm water was neutralized with acetic acid to about pH 5. The resulting precipitate was collected, washed successively with water, ethanol and ether, and then dried overnight at 80 ° C. in vacuo to give 5-carbamyl- [3,4′-biparadin] -6 (1H) -one (mp 300 ° C.) 16 g was obtained.
[실시예 4]Example 4
5-카르바밀-[3,4'-비피리딘]-6(1H)-온 제조Preparation of 5-carbamyl- [3,4'-bipyridin] -6 (1H) -one
포스겐(213㎖,98.7g,3.0몰)을 건조한 시약급 디에틸포름 아미드194㎖(25-몰)에 -10°-10℃에서 냉각하면서 적하했다. 냉각을 계속하면서 4-피콜린(93.1g,1.0몰)을 5분 이상 교반하면서 첨가했다. 이때 1시간이상 동안 발열반응이 일어나서 온도가 35-40℃로 상승했다. 혼합물을 60-65℃에서 3시간 가열교반한 후 실온까지 냉각했다. 침전된 염을 반응용기중에 그대로 두어 생성된 상청액을 흡입하여 소결된유리팁이 있는 관을 통해 배출했다. 고체를 디에틸포름아미드 200㎖씩을 2회에 걸쳐 세척하고 세척액을 흡입하여 배출했다. 회황색 결정 고체인 N-[3-디메틸 아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염을 건조한 디메틸포름 아미느 2ℓ로 처리했다.Phosgene (213 ml, 98.7 g, 3.0 mol) was added dropwise to 194 ml (25-mol) of dry reagent grade diethylformamide while cooling at -10 ° -10 ° C. 4-picoline (93.1 g, 1.0 mol) was added stirring for 5 minutes or more, continuing cooling. At this time, an exothermic reaction occurred for more than 1 hour, and the temperature rose to 35-40 ° C. The mixture was heated and stirred at 60-65 ° C. for 3 hours and then cooled to room temperature. The precipitated salt was left in the reaction vessel and the resulting supernatant was aspirated and discharged through a tube with a sintered glass tip. The solid was washed twice with 200 ml of diethylformamide, and the washing was sucked out. N- [3-dimethyl amino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride as an off-yellow crystalline solid was treated with 2 liters of dry dimethylform amine.
말론아미드(112g,1.1몰)을 교반하면서 첨가했다. 생성된 슬러리에 메톡시화 나트륨(162g,3몰)을 첨가했다. 이때 발열반응이 일어나서 온도가 24℃에서 54℃로 상승했다. 발열과 동시에 균질액으로 상변화가 일어났다. 공급물을 95一100℃에서 1시간 가열하고 10-20℃로 냉각한 후 여과했다. 가열도중 6-카르바밀-[3,4'-비피리딘]-6(1H)-은의 나트륨염이 분리되기 시작했다. 생성된 나트륨염의 필터게이크를 뜨뜻한 수도물 10ℓ에 용해하고 아세트산으로 pH를 5.5-6.5으로 조절했다. 생성된 침전물을 여과해서 모으고 물 500m1씩으로 2회에 걸쳐 세척한 후 건조(80℃, 1/3기압, 16시간)하므로서 백색-크리임색의 고체인 5-카르바밀-[3,4'-비피리딘]-6(1H)-온(m. p.>300℃)160g(수득율 74%)을 얻었다.Malonamide (112 g, 1.1 mol) was added with stirring. To the resulting slurry was added sodium methoxylated (162 g, 3 mol). At this time, an exothermic reaction occurred and the temperature rose from 24 ° C to 54 ° C. At the same time as the exotherm, a phase change occurred to the homogeneous liquid. The feed was heated at 95 ° C. 100 ° C. for 1 hour, cooled to 10-20 ° C. and filtered. During heating, the sodium salt of 6-carbamyl- [3,4'-bipyridine] -6 (1H) -silver began to separate. The filtergake of the resulting sodium salt was dissolved in 10 liters of warm tap water and the pH was adjusted to 5.5-6.5 with acetic acid. The resulting precipitate was collected by filtration, washed twice with 500m1 of water, and dried (80 ° C, 1/3 atmosphere, 16 hours) to yield 5-carbamyl- [3,4'-ratio as a white-crime-colored solid. 160 g (yield 74%) of pyridine] -6 (1H) -ones (mp> 300 degreeC) were obtained.
[실시예 5]Example 5
N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 과염소산 히드로과염소산염 제조Preparation of N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium perchloric acid hydroperchlorate
N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염 15g을 메탄올(200㎖)에 용해한 용액을 70%과염소산 5㎖로 처리하여 생성되는 혼합물을 냉각했다. 분리된 고체를 수집하여 건조하고 메탄올에서 재결정한 후 에테르로 세척하고 다시 건조하므로서 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메탈메탄이미늄과 염소산하드로 과염소산염 12g을 얻었다. 이 염을 확인 목적에 주로 사용했다. 이것의 NMR스펙트럼은 제시된 구조와 상응한것이었다.A solution of 15 g of N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride in methanol (200 ml) was treated with 5 ml of 70% perchloric acid. The resulting mixture was cooled. The separated solids were collected, dried, recrystallized from methanol, washed with ether and dried again to form N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-metalmethaneimine 12 g of perchlorate was obtained with super chloric acid. This salt was mainly used for identification purposes. Its NMR spectrum corresponded to the structure shown.
위의 과정을 되풀이함에 있어서 과염소산 대신에 메탄술폰산 같은 약학적으로 섭취가 가능한 산을 상응하는 몰당량 사용하여 싱응하는 약학적으로 섭취가 가능한 산첨가염, 즉 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메 탄이미늄메탄술폰산 또는 메탄술폰산염을 얻었다.In repeating the above procedure, a pharmaceutically acceptable acid addition salt, ie N- [3-dimethylamino-2-, is reacted using a corresponding molar equivalent of a pharmaceutically acceptable acid such as methanesulfonic acid instead of perchloric acid. (4-pyridinyl) -2-propenylidene] -N-methylmethaneimiummethanesulfonic acid or methanesulfonic acid salt was obtained.
[실시예 6]Example 6
N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리딘]-N-메틸메탄이미늄 염화물 제조Preparation of N- [3-dimethylamino-2- (4-pyridinyl) -2-propenyridine] -N-methylmethaneimium chloride
메탄올 100mℓ에 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene in 100 ml of methanol
]-N-메틸메탄이미늄 클로라이드 염산염 20g을 용해하여 C-50℃로 유지한 용액에다 메톡시화 나트륨 3.4g과 메탄올 25㎖로 된용액을 적하했다. 분리된 염화나트륨을 여과하고 여액을 30-40℃의 진공에서 처리하여 용매를 제거했다. 고체 잔류물을 아세트산 에틸에서 슬러리로 만들고 여과한 후 에테르로 세척하여 건조했다. 고체를 아세트니트릴에서 재결정하고 에테르로 세척한 후 진공에서 80℃에서 하루밤 건조하므로서 N-[3-디메틸아미노-2-(4-피리딘일(-2-프로페닐리덴-N-메틸메탄이미늄 염화물(m. p.233-235℃)5g을 얻었다. 이 화합물의 NMR스펙트럼은 제시된 구조의 것과 상응했다.To a solution containing 20 g of] -N-methylmethaneimium chloride hydrochloride dissolved at C-50 ° C., a solution of 3.4 g of sodium methoxide and 25 ml of methanol was added dropwise. The separated sodium chloride was filtered and the filtrate was treated in vacuo at 30-40 ° C. to remove the solvent. The solid residue was slurried in ethyl acetate, filtered and washed with ether and dried. The solid was recrystallized from acetonitrile and washed with ether and then dried overnight at 80 ° C. in vacuo, thereby N- [3-dimethylamino-2- (4-pyridinyl (-2-propenylidene-N-methylmethanimium chloride) 5 g (mp233-235 ° C.) The NMR spectrum of this compound corresponded to that of the structure shown.
분리해낸 고양이 심방(心房)과 유두근(乳頭筋)의 수축력을 상당히 증가시키는 표준 심장기는 시험에서의 효과에서 강심제로서의 효능이 나타나므로서 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄염(I)또는 이것의The standard cardiac phase, which significantly increases the contractile force of the isolated cat's atria and papillary muscles, shows its efficacy as a cardiac agent in the effects of the test, with N- [3-dimethylamino-2- (4-pyridinyl) 2-propenylidene] -N-methylmethaneimium salt (I) or its
약학적으로 섭취가능한 산첨가염의 효용성이 증명되었다. 이시험 방법에 대한 구체적인 것은 미극특허 제4,072,746호에 나와 있다.The effectiveness of pharmaceutically acceptable acid addition salts has been demonstrated. Details of this test method are described in US Pat. No. 4,072,746.
위에 나온 분리된 고양이의 심방과 유두근에 대한 시험에 있어서 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메틸메탄이미늄 클로라이드 염산염 ( I ) 을 100ug/㎖ 및 300ug/㎖ 투여했을때 유두근의 힘이 25%이상으로 증가했고 오른쪽 심방의 힘은 약 13-22%사이에서 보다 작게 증가한 반면 오른쪽 심방속도는(유두근의 힘과 오른쪽 심방힘 보다)작게 증가했다.N- [3-dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-methylmethanimium chloride hydrochloride (I) was tested for the atrial and papillary muscles of the above isolated cats. At 100 ug / ml and 300 ug / ml, the power of the papilla increased by more than 25% and the strength of the right atrium increased smaller than between about 13-22%, while the right atrial velocity (rather than the power of the papilla and right atrial). Increased small.
본 발명은 심장 수축성을 증가시키는 강심제 조성물을 포함하는데, 이 조성물은 약학적으로 섭취가 가능한 운반체와 이것의 활성 성분으로서 강심제인 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메털메탄이미늄 염(I) 또는 이것의 약학적으로 섭취가 가능한 산첨가염으로 되어 있다. 치료에 있어서 이 화합물 또는 이것의 염은 광범위한 제형(劑杉)으로 경구 또는 비경구적으로 투여하는 것이 보통이다.The present invention includes a cardiac agent composition that increases cardiac contractility, which composition is a pharmaceutically acceptable carrier and its active ingredient N- [3-dimethylamino-2- (4-pyridinyl) -2 -Propenylidene] -N-metalmethaneimine salt (I) or a pharmaceutically acceptable acid addition salt thereof. In treatment, the compound or salt thereof is usually administered orally or parenterally in a wide range of formulations.
경구투여용 조성물로는 압축정제, 환제, 분말 및 과립이 있다. 이러한 고체 조성물에 있어서 최소한 한가지 활성 화합물을 녹말, 탄산칼슘, 수크로오스 또는 락토오스 같은 비활성 부형제를 최소한 한가지와 혼합한다. 이들 조성물에 비활성 물질이외에 스테아르산 마그네슘, 활성등과 같은 윤활제릍 추가로 혼합할 수도 있다.Compositions for oral administration include compressed tablets, pills, powders, and granules. In this solid composition at least one active compound is mixed with at least one inert excipient such as starch, calcium carbonate, sucrose or lactose. In addition to the inert substances, these compositions may be further mixed with lubricants such as magnesium stearate, activity and the like.
경구투여용 액체 조성물에는 물과 액체파리핀 같은 종래에 보편적으로 사용되던 비활성부형제를 함유한엘릭시르, 시럽, 현탁액, 용액 및 에멀션이 있다. 비활성 부형제외에 이 조성물중에 습윤제와 현탁제, 감미제, 향미제, 향료, 보조제 등의 보조제를 첨가할 수도 있다.Liquid compositions for oral administration include elixirs, syrups, suspensions, solutions and emulsions containing inert excipients commonly used conventionally, such as water and liquid paraffin. In addition to the inert excipients, it is also possible to add auxiliaries such as wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances, adjuvants and the like.
본 발명에 의하여 경구투여용 화합물에는 흡수성 물질로 된 캡슐, 즉 젤라틴 같은 것에 부형제를 첨가하거나 첨가하지 않고, 활성물질을 첨가해서 만든것도 있다. 비경구용으로서 본 발명에 의한 것으로는 무균액,유기수용액, 무기수용액, 현탁액 및 에멀션이 있다. 유기 용매 또는 현탁 매체의 예로는 프로필렌글리콜, 폴리에틸렌 글리콜, 식물성 기름(예 : 올리브 기름) 및 주사용 유기 에스테르(예 : 올레산에틸)이 있다. 이들 조성물중에 안정제, 방부제, 습윤제, 유화제 및 분산제 같은 보조제를 첨가할 수도 있다.According to the present invention, the compound for oral administration may be made by adding an active substance to the capsule of absorbent substance, ie, gelatin, with or without an excipient. For parenteral use, there are sterile liquids, organic aqueous solutions, inorganic aqueous solutions, suspensions and emulsions. Examples of organic solvents or suspending media include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Supplements such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants may also be added to these compositions.
이 조성물은 세규통과 억제 여과기를 통해 여과하거나 조성물중에 멸균제를 가하던지 방사선 조사 또는 가열에 의해 살균한다. 또한 멸균수나 기타 주사용 멸균 매체중에 용해하여 즉시 사용할 수 있는 멸균 고체 조성물 형태로 제조할 수도 있다.The composition is sterilized by filtration through a microfluidic and suppression filter or by applying a sterilant to the composition or by irradiation or heating. It may also be prepared in the form of a sterile solid composition which can be dissolved in sterile water or other sterile injectable medium and ready for use.
이 조성물중의 활성 성분의 량(%)과 심장수축성을 증가시키는 방법을 변화시키므로서 적당한 용량으로 만들수 있다. 특수한 환자에 투여되는 용량을 의사의 처방에 따라 조절할 수도 있다. 즉 투여경로 치료기간, 환자의 조건과 신체크기, 활성성분의 역가와 환자의 약에 대한 반응등을 고려하여 투여량을 정한다. 따라서 모든 기준을 고려하고 환자에 대한 최초의 판단을 의사가 하므로서 활성 성분의 유효 투여량을 결정한다.It can be made in a suitable dose by varying the amount of active ingredient in this composition (%) and the method of increasing cardiac contractility. The dose administered to a particular patient may be adjusted according to the doctor's prescription. In other words, the dosage is determined in consideration of the duration of the administration route, the condition and body size of the patient, the titer of the active ingredient and the patient's response to the drug. Therefore, the effective dosage of the active ingredient is determined by considering all the criteria and making the initial judgment of the patient.
본 발명은 30℃이하에서 4-피콜린과 이러한 4-피콜린 1몰당 옥시염화인 같은 무기산 할로겐화물 최소한 3당량과 과잉량의 디메틸 포름아미드를 반응시키고, 미분리된 생성물인 N-[3-디메틸아미노-2-(4-피리딘일)-2-프로페닐리덴]-N-메탈메탄이미늄염(pH를 약 8.0으로 조절하여 침전된 무기 양이온염을 여과해 버린 것)과 과잉량의 2-시아노 아세트 아미드를 용액중에서 반응시킨후 최소한 3몰 당량의염기와 반응시켜 5-시아노-[3,4'-비피리딘]-6(1H)-피리딘온을 유리염기 형태(증화시킨 후의 것) 또는 무기 양이온염의 형태로 분리하는 방법에 관한 것이다.The present invention reacts 4-picoline with at least 3 equivalents of an inorganic acid halide such as phosphorus oxychloride per mole of 4-picoline and an excess of dimethyl formamide at 30 ° C. or lower. Dimethylamino-2- (4-pyridinyl) -2-propenylidene] -N-metalmethanimium salt (adjusting the pH to about 8.0 and filtering out the precipitated inorganic cation salt) and excess 2- After reacting cyano acetamide in solution with at least 3 molar equivalents of base, 5-cyano- [3,4'-bipyridine] -6 (1H) -pyridinone in freebase form Or in the form of an inorganic cationic salt.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/124,808 US4264609A (en) | 1980-02-26 | 1980-02-26 | N-[3-Dimethylamino-2-(4-pyridinyl)-2-propenylidene]-N-methylmethaniminium chloride hydrochloride, its use in preparing 5-(cyano or carbamyl)-[3,4'-bipyridin]-6(1H)-one and its use as a cardiotonic |
| KR1019810000616A KR840002067B1 (en) | 1980-02-26 | 1981-02-25 | Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one |
| US124,808 | 1987-11-24 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019810000616A Division KR840002067B1 (en) | 1980-02-26 | 1981-02-25 | Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR840002066B1 true KR840002066B1 (en) | 1984-11-09 |
Family
ID=22416880
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019810000616A KR840002067B1 (en) | 1980-02-26 | 1981-02-25 | Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one |
| KR1019840005058A KR840002066B1 (en) | 1980-02-26 | 1984-08-22 | Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019810000616A KR840002067B1 (en) | 1980-02-26 | 1981-02-25 | Process for preparation of 5-q-(3,4'-bipyridine)-6(1h)-one |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US4264609A (en) |
| JP (1) | JPS56128758A (en) |
| KR (2) | KR840002067B1 (en) |
| AR (1) | AR230630A1 (en) |
| AT (2) | AT380237B (en) |
| AU (1) | AU541644B2 (en) |
| BE (1) | BE887663A (en) |
| CA (1) | CA1128523A (en) |
| CH (1) | CH647509A5 (en) |
| DE (1) | DE3107306A1 (en) |
| DK (1) | DK171253B1 (en) |
| ES (1) | ES499776A1 (en) |
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| IE (1) | IE51696B1 (en) |
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| LU (1) | LU83169A1 (en) |
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| NL (1) | NL192109C (en) |
| NO (1) | NO156689C (en) |
| NZ (1) | NZ196282A (en) |
| PH (2) | PH19904A (en) |
| PT (1) | PT72573B (en) |
| SE (2) | SE437514B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0200024B1 (en) | 1985-04-30 | 1992-07-01 | ARZNEIMITTELWERK DRESDEN GmbH | 3-cyano-pyridines, process for their preparation and their pharmaceutical use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072746A (en) * | 1975-10-14 | 1978-02-07 | Sterling Drug Inc. | 3-Amino-5-(pyridinyl)-2(1H)-pyridinones |
| US4004012A (en) * | 1975-10-14 | 1977-01-18 | Sterling Drug Inc. | 3-Cyano-5-(pyridinyl)-2(1H)-pyridinones |
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